Biphenyl compounds and their use as oestrogenic agents

ABSTRACT

A method of treating symptoms linked to menopause in warm-blooded animals by administering to warm-blooded animals in need thereof an amount of a compound of the formula  
                 
 
     wherein the substituents are defined as in the application sufficient to treat said symptoms.

[0001] A subject of the invention is new biphenyl compounds, theirpreparation process and the intermediates of this process, their use asmedicaments and the pharmaceutical compositions containing them.

[0002] A subject of the invention is the compounds of general formula(I):

[0003] in which [X] represent the following aromatic carbocycles:

[0004] in which R₁ represents an alkyl radical containing from 1 to 4carbon atoms or a hydrogen-atom, R₂ represents an alkyl radicalcontaining from 1 to 4 carbon atoms or a hydrogen atom, R₃ represents ahydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms,R₄ in para or meta position represents a hydrogen atom, a halogen atom,a hydroxyl radical, an alkyl, alkenyl or alkynyl radical containing atmost 4 carbon atoms, an alkoxy, alkylthio radical in which alkylcontains from 1 to 4 carbon atoms, an —NR_(A)R_(B) group in which R_(A)and R_(B) identical or different represent a hydrogen atom, an alkylradical containing from 1 to 4 carbon atoms or form together with thenitrogen to which they are linked a saturated heterocycle with 5 or 6members optionally containing a second heteroatom chosen from nitrogen,oxygen and sulphur, their —NR_(A)R_(B) group being optionally inoxidized form, a group of general formula —O—(CH₂)_(n)—NR_(A)R_(B) inwhich n is an integer which varies from 2 to 7 and in which —NR_(A)R_(B)is as defined previously, R₅ represents a hydrogen atom or a halogenatom, R₆ and R₇ identical or different represent a hydrogen atom, ahalogen atom, an alkyl radical containing from 1 to 4 carbon atoms, or aphenyl radical optionally substituted in meta or para position by an R₄radical as defined previously as well as the addition salts with acidsor bases, with the exception of the compounds of formula (I) in which[X] represents the group (A) in which R₁, R₂, R₃ are hydrogen atoms andR₄ represents a hydroxyl radical and those in which [X] represents thegroup (B) in which R₅, R₆ and R₇ are hydrogen atoms or R₅ and R₆ arehydrogen atoms and R₇ represents an alkyl radical containing from 1 to 4carbon atoms.

[0005] When R₁, R₂, R₃, R₄, R₆, R₇, R_(A) and R_(B) represent an alkylradical containing from 1 to 4 carbon atoms, it is a methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert-butyl radical. When R₃, R₄,R₅, R₆ and R₇ are halogen atoms, it is fluorine, chlorine, bromine oriodine. Preferably, it is chlorine. When R₄ is an alkenyl radicalcontaining at most 4 carbon atoms, preferably it is a vinyl or propenylradical. When R₄ is an alkynyl radical containing at most 4 carbonatoms, preferably it is an ethynyl or propynyl radical. When R₃ or R₄represent an alkyloxy radical containing from 1 to 4 carbon atoms,preferably it is a methoxy, ethoxy, propyloxy, isopropyloxy or butyloxyradical. When R₄ is an alkylthio radical containing from 1 to 4 carbonatoms, preferably it is a methylthio, ethylthio, propylthio,isopropylthio or butylthio radical. When R₄ is an NR_(A)R_(B) radical inwhich R_(A) and R_(B) identical or different represent a hydrogen atomor an alkyl radical containing from 1 to 4 carbon atoms, preferably itis an amino, methylamino, ethylamino, dimethylamino, diethylamino ormethylethylamino radical. When R₄ is an —NR_(A)R_(B) group in whichR_(A) and R_(B) form with the nitrogen a saturated heterocycle,preferably it is pyrrolidino, piperidino, piperazino, morpholino orthiomorpholino groups, each of these amino groups being optionally inoxidized form.

[0006] Naturally the invention extends to the salts of the compounds deformula (I), in particular when the compounds of formula (I) contain anamino function. These are the salts formed for example with thefollowing acids: hydrochloric, hydrobromic, nitric, sulphuric,phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric,succinic, tartaric, citric, oxalic, glyoxylic, aspartic,alkanesulphonics such as methane- and ethanesulphonics, arenesulphonics,such as benzene and paratoluene sulphonics and arylcarboxylics.

[0007] These are also the salts formed under the action of a base or analkali or alkaline-earth metal, in order to obtain for examplederivatives such as sodium or potassium alcoholate or derivatives suchas potassium or sodium phenolate.

[0008] A more particular subject of the invention is the compounds ofgeneral formula (I) as defined previously in which [X] is the aromaticcarbocycle of general formula (A).

[0009] A more particular subject of the invention is the products ofgeneral formula (I) as defined previously in which [X] is the aromaticcarbocycle of general formula (B).

[0010] A more particular subject of the invention is the products ofgeneral formula (I) as defined above, corresponding to general formula(I′):

[0011] in which R′₁, R′₂ and R′₃ represent a hydrogen atom or an alkylradical containing from 1 to 4 carbon atoms, R′₄ in meta or paraposition represents a hydrogen atom, a halogen atom, a hydroxyl radical,an alkyl radical, an —NR_(A)R_(B) group or an —O—(CH₂)_(n)—NR_(A)R_(B)group, n, R_(A) and R_(B) being as defined previously, as well as theaddition salts with acids. When R′₄ is an —O—(CH₂)_(n)—NR_(A)R_(B)group, it is preferably the —O—(CH₂)₂—NMe₂ group.

[0012] A more particular subject of the invention is the products ofgeneral formula (I) as defined previously corresponding to generalformula (I′) in which R′₁, R′₂ and R′₃ are hydrogen atoms.

[0013] A quite particular subject of the invention is the compound ofgeneral formula (I) as defined previously in which R₆ represents ahalogen atom or an

[0014] —O—(CH₂)₂—N(CH₃)₂ group and R₇ represents a hydrogen atom.

[0015] A quite particular subject of the invention is the compound ofgeneral formula (I) as defined above the names of which follow:

[0016] 5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol,

[0017] 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,

[0018] 5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol.

[0019] A subject of the invention is also a preparation process for theproducts of formula (I) as defined above characterized in that a productof formula (II):

[0020] in which [X] is as defined previously, P′ represents a protectivegroup, and G represents a halogen atom or an OSO₂CF₃ group is subjectedto the action, in the presence of a catalyst, of a product of formula(III):

[0021] in which Y represents a halogen atom, a B(OH)₂ group or an Sn(R)₃group, in which R represents an alkyl group containing from 1 to 8carbon atoms and P represents a protective group identical to ordifferent from P′, in order to obtain a product of formula (IV):

[0022] in which P, P′ and [X] have the same meaning as previously, whichproduct of formula (IV) is subjected to one or more deprotectionreactions in order to obtain the product of formula (I) as definedpreviously which, if appropriate is subjected to the action of an acidor base in order to obtain the corresponding salt.

[0023] The formation of the biphenyls of formula (IV) by coupling thearomatic compound of formula (II) with the aromatic compound of formula(III) is carried out in the presence of a catalyst chosen from thederivatives of palladium or in the presence of copper in the case whereY is an iodine atom and can therefore be carried out under theconditions described in the following articles:

[0024] A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679:Conditions: Na₂CO₃ 2M/Pd(PΦ₃)₄/Toluene/LiCl/EtOH/Δ)

[0025] J. K. Stille Ang. Chem. Int. Ed. (1986) 25 508: Conditions:Pd(PΦ₃)₄/LiCl/Dioxane/Δ)

[0026] T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 582201-2208: Conditions: K₃PO₄/KBr/Pd(PΦ₃)₄/Dioxane/Δ)

[0027] P. E. Fank Chem. Rev. (1964) 38 139: Conditions: Cu/DMF/120° C.in the case where Y is an iodine atom.

[0028] E. Erdik Tetrahedron (1992) 48 9577: Conditions: nBuLi/THF/−78°C.-2) ZnCl2-3) ArBr/Pd(PΦ₃)₄/)Δ4)HCl/MeOH.

[0029] A subject of the invention is also a preparation process forproducts of formula (I) in which [X] is the aromatic carbocycle offormula (A) as defined above characterized in that a product de formula(V):

[0030] in which R₄ and P are as defined previously, is subjected to theaction of the methylvinylketone of general formula (VI):

[0031] in which R₁, R₂ and R₃ are as defined previously, in order toobtain the product of formula (VII):

[0032] in which R₁, R₂, R₃, R₄ and P are as defined previously, which issubjected to the action of a dehydration and aromatization reagent inorder to obtain the product of formula (VIII):

[0033] in which R₁, R₂, R₃, R₄ and P are as defined previously, which issubjected to the action of a deprotection reagent in order to obtain theproducts of formula (I) in which [X] is the aromatic carbocycle offormula (A) which, if desired, is subjected to the action of an acid inorder to obtain a corresponding salt.

[0034] The protective groups P or P′ are preferably chosen from an alkylradical containing from 1 to 4 carbon atoms, a benzyl group and anRCRDRESi group, in which Rc, RD and RE identical or different representan alkyl radical containing from 1 to 4 carbon atoms or a phenyl group.It will be quite particularly methyl, phenyl, terbutyldimethylsilyl andterbutyldiphenylsilyl radicals.

[0035] The action of the methylvinylketone of general formula (III) onthe product of formula (II) is preferably carried out in the presence ofa base such as potash in a dioxane/water mixture.

[0036] The dehydration and aromatization reaction is carried out forexample using a mineral acid such as phosphoric acid at a temperature of150° C. for 4 hours.

[0037] The deprotection reactions are the standard deprotection methodsknown to a person skilled in the art. A fairly complete list is found inthe following work: Protective groups in organic synthesis T. W greene,John Wiley & sons (1981).

[0038] By way of example, when P or P′ represent a methyl radical thedeprotection reaction can be carried out by the action of tribromoboranein dichloromethane or hydrochloric acid in pyridine. When P or P′represents a benzyl group a catalytic hydrogenation or a hydrolysis canbe carried out with trifluoroacetic acid. When P or P′ represents asilyl group the deprotection can be carried out with tetra-butylammoniumfluoride (TBAF) in tetrahydrofuran (THF).

[0039] Salification by an acid or a base is carried out under standardconditions. The operation is carried out for example with hydrochloricacid, in an ethereal solution.

[0040] The compounds of formula (I) as well as their addition salts withpharmaceutically acceptable acids or bases are particularly usefulproducts from a pharmacological point of view.

[0041] They are the original ligands of the oestrogen receptor. As such,they can be used in the treatment of disorders linked tohypofolliculinia, for example, amenorrheas, dysmenorrheas, repeatedabortions, premenstrual disorders, in the treatment of certainoestrogen-dependent pathologies such as prostatic adenomas orcarcinomas, mammary carcinomas and their metastases or in the treatmentof benign tumors of the breast, both as an antiuterotrophic as well asin replacement treatment of symptoms linked to the menopause and inparticular osteoporosis.

[0042] Therefore, a subject of the invention is, as medicaments, theproducts of formula (I) as described previously as well as theiraddition salts with pharmaceutically acceptable acids or bases.

[0043] A more particular subject of the invention is, as medicaments,the compounds of formula (I) as described previously corresponding togeneral formula (I′) as described previously as well as the additionsalts with pharmaceutically acceptable acids or bases.

[0044] A quite particular subject of the invention is, as medicaments,the following products of formula (I):

[0045] 5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxy-phenyl)2-naphthalenol,

[0046] 5-chloro-6-(4-hydroxyphenyl)₂-naphthalenol,

[0047] 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol.

[0048] The invention extends to the pharmaceutical compositionscontaining at least one medicament as defined above as activeingredient.

[0049] The compositions of formula (I) are used by digestive, parenteralor local route, for example by percutaneous route. They can beprescribed in the form of plain or sugar-coated tablets, capsules,granules, suppositories, pessaries, injectable preparations, ointments,creams, gels, microspheres, implants, patches which are preparedaccording to the usual methods.

[0050] The active ingredient or ingredients can be incorporated withexcipients usually employed in these pharmaceutical compositions, suchas talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter,aqueous or non-aqueous vehicles, fatty substances of animal or vegetableorigin, paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, preservatives.

[0051] The dose varies according to the illness treated and theadministration route: it can be, for example, from 1 mg to 100 mg perday by oral route, for an adult.

[0052] The products of general formula (V) as defined above are obtainedby the action of the product of general formula (IX):

[0053] with a product of general formula (X):

[0054] in the presence of a strong base such as LDA (lithiumdiisopropylamide).

[0055] This reaction is described in:

[0056] S. HUNIG et al. Chem. Ber. (1980) 113, 324-332

[0057] The products of formula (X) are obtained by the action oftrimethyl silyl cyanide in the presence of a Lewis acid such as ZnI₂, onthe corresponding aldehyde of general formula (XI):

[0058] This reaction is described in Synthesis (1980) p. 861-868. Theprotected products of formula (IX) are obtained from parahydroxybenzaldehyde by standard protection methods for alcohols described inthe work by T. W. Greene mentioned above.

[0059] The products of formulae (II), (III), (IX), (X) and (XI) arecommercial products or are easily accessible by standardfunctionalization methods for aromatic compounds known to a personskilled in the art.

[0060] The products of formula (VI) are also easily accessible to aperson skilled in the art.

[0061] The products of formula (V) in which R₄ is an alkyloxy containingfrom 1 to 4 carbon atoms in para position and P is an alkyl containingfrom 1 to 4 carbon atoms, are known and are described in the followingreferences:

[0062] Chemical Abstract: 65-10442b, 112-148858n, 59-9865f.

[0063] Finally, a subject of the invention is, as new industrialproducts and in particular as new intermediate products necessary forthe implementation of the invention, the products of general formulae(IV), (V), (VII) and (VIII) as defined previously, with the exception ofthe products of formula (V) in which R₄ is an alkyloxy containing from 1to 4 carbon atoms or a halogen atom and P is an alkyl radical containingfrom 1 to 4 carbon atoms and with the exception of the products deformulae (VII) and (VIII) in which R₄ is a methoxy radical, P is amethyl radical and R₁, R₂ and R₃ are hydrogen atoms, and with theexception of the products of formula (IV) in which P and P′ are methylor acyl radicals, X represents the group B in which R₅, R₆ and R₇ arehydrogen atoms.

[0064] The following examples illustrate the invention without howeverlimiting it:

Preparation 1 [4-(phenylmethoxy)phenyl]-boronic acid Stage A:1-bromo-4-(phenylmethoxy)-benzene

[0065] 15.26 g of sodium hydride at 50% in oil is added at 0° C. to asolution under inert gas of 50 g of parabromophenol in 320 ml ofdimethylformamide (DMF), agitation is carried out for 30 minutes at 0°C., then 37.7 ml of benzyl bromide is added. Agitation is carried outfor 2 hours 30 minutes while allowing the temperature to rise to 20° C.,then the reaction mixture is poured into ice-cooled water, theprecipitate is filtered, and dried. 73.35 g of expected product isobtained. Rf: 0.85 (thin layer chromatography, support: silica, eluant:cyclohexane/ethyl acetate 7/3).

[0066] I.R. spectrum: (CHCl₃) Absence of OH Aromatic 1592, 1580 and 1488cm⁻¹

Stage B: [4-(phenylmethoxy)phenyl]-boronic acid

[0067] 143 ml of a solution of n-Butyllithium (nBuLi) is added dropwise,under inert gas and at −78° C., to 47.08 g of the product obtained inStage A in 375 ml of tetrahydrofuran (THF), agitation is carried out for1 hour, then 36.5 ml of triethylborate is added. Agitation is carriedout for 14 hours, while leaving the temperature to rise to 20° C., andthe reaction medium is hydrolyzed using a solution of ice-cooled watercontaining 45 ml of concentrated sulphuric acid, for 1 hour at 20° C.The aqueous phase is extracted with ethyl acetate, the organic phasesare washed with 2N soda and the aqueous phase is acidified to pH=l usinga 1N solution of hydrochloric acid in order to precipitate the boronicacid. After filtration and drying the precipitate 28.54 g of expectedproduct is obtained. Rf: 0.16 cyclohexane/ethyl acetate 7/3) I.R.spectrum: (Nujol) General absorption 3650, 3615, 3510 and 3420 cm⁻¹OH/NH region Aromatic 1605, 1570 and 1510 cm⁻¹ B—O 1410, 1340 cm⁻¹

Preparation 2 [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]phenyl]-boronicacid Stage A: 1-Bromo-4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]benzene

[0068] 400 ml of dimethylformamide, 31:18 g of imidazole and 125.89 g of1,1-dimethyl-ethyl-diphenyl-chlorosilane are added under an inertatmosphere and at ambient temperature to 80.89 g of parabromophenol,then the solution obtained is agitated for 2 hours. The reaction mediumis poured into 2 liters of water, precipitation is observed, the solidis solubilized with ethyl acetate and the aqueous phase is extractedwith ethyl acetate, the combined organic phases are dried and evaporatedunder reduced pressure until an oil is obtained. Pentane is added andcrystallization is observed. After filtration and drying the precipitate179.24 g of expected product is obtained. Rf: 0.53 (thin layerchromatography, support: silica, eluant Cyclohexane/AcOEt 95/5).

[0069] Melting point: 56° C. NMR (CDCl₃, 300 MHz) 1.09 s SitBu 6.63 mH₃, H₅ 7.17 m H₂, H₆ 7.69 dd 4H for SiΦ2 7.4 6H for SiΦ2

Stare B: [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy] phenyl]-boronic acid

[0070] 60 ml of a solution of n-butyl-lithium is added dropwise at −78°C. and under inert gas to a solution of 30 g of the product of thepreceding stage in 100 ml of anhydrous tetrahydrofuran, then afteragitation for 30 minutes at −78° C., 9.95 ml of trimethylborate isadded. After agitation for 2 hours 30 minutes, the bath temperaturehaving risen to 11.9° C., 20 ml of water is added dropwise and agitationis carried out for 72 hours at ambient temperature. After evaporation ofthe tetrahydrofuran under reduced pressure, the aqueous phase isextracted with ether, followed by drying and concentrating under reducedpressure until an oil is obtained (26.35 g) which is purified byfiltration chromatography on silica with a hexane/ethyl acetate mixture1/1 in order to obtain 7.73 g of expected product in the form of thedimer.

[0071] IR (CHCl₃) O—Si 915 and 1255 cm⁻¹ B—O 1350 and 1370 cm⁻¹Aromatics 1515, 1570 and 1602 cm⁻¹ NMR (CDCl₃) 1.11 tBu 6.81 and 7.88Ph-O 7.3 to 7.5 (6H) and 7.72 (4H) PhSi

Preparation 3 (4-methoxyphenyl)-boronic acid

[0072] 100 ml of a solution of 10 g of p-bromoanisole in anhydrousdiethyl ether is added dropwise under reflux to a suspension, underinert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethylether, and the mixture is left under reflux for 2 hours. The reactionmedium is then poured into a solution of 9.02 ml of triethylborate in 60ml of anhydrous ether cooled down to −70° C. After agitation for 1 hourat −70° C., then for 1 hour at ambient temperature, the solution ispoured into a mixture containing 11 ml of sulphuric acid and 50 g of iceand water and agitation is carried out for 1 hour. The organic phase isextracted with 100 ml of a saturated aqueous solution of sodiumbicarbonate, the aqueous phases are combined, reacidified with 6Nhydrochloric acid, extracted with ether, dried and evaporated underreduced pressure. 3.9 g of expected product is obtained.

[0073] I.R. spectrum: (Nujol) Complex absorption OH/NH region, 1609,1573 and 1518 cm⁻¹ NMR (DMSO-d6, 300 MHz) 3.76 s OCH ₃ 6.88 d J = 9 HzH₃ and H₅ 7.78 d J = 9 Hz H₂ and H₆ 7.86 B(OH)₂

Preparation 4 4-(dimethylaminoethoxy) phenyl boronate

[0074] 2.5 g of 1-bromo 4-(dimethylamino) ethoxy benzene described inthe Patent RO 83118 in 50 ml of tetrahydrofuran is cooled down to −78°C. then 7.86 ml of n-butyllithium is added over 5 minutes. Agitation iscarried out for 30 minutes at −78° C., 1.35 ml of trimethyl borate isadded over 10 minutes, the reaction medium is maintained for 2 hoursunder agitation at −78° C. then for 3 hours at ambient temperature. 3 mlof water is added dropwise and agitation is carried out for 72 hours atambient temperature. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant THF) then onneutral alumina (eluant: CH₂Cl₂ then CH₂Cl₂—MeOH 95-5). 810 mg ofexpected product is obtained. Rf=0.2 (CH₂Cl₂—MeOH 95-5).

EXAMPLE 1 5-[-4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol Stage A: 1-[4-[2-(dimethylamino) ethoxy] phenyl]6-methoxy 2-naphthalenol

[0075] a) 1-bromo 6-methoxy 2-naphthalenol. 1.05 g of 6-methoxy2-naphthalenol prepared as in Example 2 Stage A in 15 ml of ethanol,0.84 g of N-bromoacetamide is added and agitation is carried out for 1hour at ambient temperature. The reaction medium is poured into 800 mlof water followed by extraction with methylene chloride, drying, thesolvent is evaporated off under reduced pressure, the residue ispurified by chromatography on silica (eluant:cyclohexane-dichloromethane 50-50). 0.75 g of expected product iscollected.

[0076] b) 2.5 g of the product obtained as in Stage a) with 2,45 g of4-(dimethylaminoethoxy) phenyl boronate prepared as indicated inPreparation 4 in 150 ml of dioxane is agitated under reflux for 3 hoursin the presence of 0.85 g of palladium tetrakis and 3.8 g of potassiumphosphate mono-hydrate. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 95-5) and 1.8 g of expected product isobtained.

Stare B 1-[4-(2-dimethylamino) ethoxy] phenyl] 6-methoxy 2-naphthalenoltrifluoromethanesulphonate

[0077] 1 g of the product obtained in Stage A is mixed with 30 ml ofpyridine then 1.25 ml triflic anhydride is added. The reaction medium isheated for 3 hours at 80° -90° C., then poured into a saturated aqueoussolution of sodium bicarbonate. Extraction is carried out with ethylacetate, followed by drying, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:cyclohexane-ethyl acetate 7-3 then dichloromethane-methanol 95-5). 0.72g of expected product is obtained.

[0078] Rf=0.3 (eluant: CH₂Cl₂-CH₃OH95-5).

Stare C: N,N-dimethyl 2-(4-[6-methoxy 2-(4-methoxyphenyl)1-naphthalenyl] phenoxy] ethanamine

[0079] 0.64 g of the triflate obtained in Stage B with 274 mg of4-methoxyphenyl boronic acid prepared as indicated in Preparation 3 in30 ml of dimethylformamide is heated for 3 hours at 120° C. in thepresence of 32 mg of dipalladium tris(dibenzylideneacetone), 505 mg ofpotassium phosphate monohydrate, 177 mg of potassium bromide and 73 mgof triphenylphosphine. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 95-5 then ethyl acetate-acetone-methanol80-10-10). 0.28 g of expected product is obtained.

Rf=0.16 (AcOEt-(CH₃)₂CO—CH₃OH 80-10-10) IR spectrum (CHCl₃) aromatic:1625, 1610, 1600, 1572, 1515, 1499 cm⁻¹. Stage D:5-[-4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol

[0080] 95 mg of the product obtained as in Stage C is heated for 1 hourat 200° C. with 1.2 g of pyridinium hydrochloride, followed by taking upin a saturated aqueous solution of sodium bicarbonate, extraction withethyl acetate and drying, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 90-10) and 35 mg of expected product isobtained.

[0081] Rf=0.07 (AcOEt-(CH₃)₂—CO—CH₃OH 80-10-10). IR spectrum (Nujol)aromatic: 1620, 1608, 1508 cm⁻¹

EXAMPLE 2 5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol Stage A:protection of the naphthol 2-hydroxy-6-methoxy-naphthalene

[0082] 3.75 ml of methyl sulphate and 0.8 g of soda are added, under aninert atmosphere to 3.2 g of 2,6-dihydroxy-naphthalene in 20 ml ofmethanol and 3 ml of water, and the reaction medium is heated for 15hours at 40° C. After having poured the reaction medium into 200 ml ofwater, extraction is carried out with ethyl acetate, followed by drying,filtering and evaporating under reduced pressure. The crude product ispurified by chromatography and 1.2 g of expected product is obtained aswell as 1.6 g of biprotected analogue.

[0083] Rf=0.24 (cyclohexane/ethyl acetate 80/20) NMR (CDCl₃) 3.90 (s)OCH₃ 4.89 (ws) OH 7.58 d; 7.64 d H₄; H₈ 7.03 to 7.15 m 4H H₁, H₃, H₅, H₇

Stage B: Chlorination 1-chloro-2-hydroxy-6-methoxy-naphthalene

[0084] 175 mg of the product prepared in the preceding stage is addedunder an inert atmosphere to a solution of thionyl chloride in 5 ml ofchloroform at ambient temperature and agitation is carried out for 1hour. After washing with water, drying, filtration and evaporation underreduced pressure, 200 mg of expected product is obtained.

[0085] Rf=0.25 (cyclohexane/ethyl acetate 70/30) NMR (CDCl₃) 3.91 s OCH₃5.71 s OH 7.59 d; 7.97 d H₄; H₈ 7.23 m H₃ 7.11 d J = 2, 5 Hz H₅ 7.23 mH₇

Stage C: formation of the triflate1-chloro-2-trifluoromethylsulphonyloxy-6-methoxy-naphthalene

[0086] 0.75 ml of triflic anhydride is added at 0° C. to a solution,under an inert atmosphere of 600 mg of the chloronaphthol obtained inthe preceding stage in 50 ml of pyridine, and agitation is carried outfor 1.5 hours at ambient temperature. The reaction medium is then pouredinto 300 ml of water, followed by extraction with ethyl acetate, drying,filtering then evaporation under reduced pressure. 1 g of expectedproduct is obtained which used as it is in the following stage.

[0087] Rf=0.28 (cyclohexane/ethyl acetate 70/30)

Stage D: Coupling1-chloro-2-(4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]phenyl)-6-methoxy-naphthalene

[0088] A mixture constituted by 1 g of the triflate prepared in thepreceding stage, 1.5 g of the boronic acid obtained in Preparation 2,420 mg of potassium bromide, 1.1 g of potassium phosphate monohydrate,100 mg of palladium tetrakis and 50 ml of dioxane are mixed together for8 hours, under an inert atmosphere, under reflux. After washing withwater, drying, filtration then evaporation under reduced pressure, thecrude product is purified by chromatography eluting with acyclohexane/ethyl acetate mixture 97/3. 1.4 g of expected product isobtained.

[0089] Rf=0.55 (cyclohexane/ethyl acetate 90/10)

Stage E: Deprotection (desilylation)1-chloro-2-(4-hydroxyphenyl)-6-methoxy-naphthalene

[0090] 700 mg of the product obtained in the preceding stage in 50 ml oftetrahydrofuran and 1.5 ml of tetrabutylammonium fluoride (1M/THF) areagitated for 30 minutes, under an inert atmosphere and at ambienttemperature. After evaporation under reduced pressure, the crude productis purified by chromatography eluting with a cyclohexane/ethyl acetatemixture 90/10. 300 mg of expected product is obtained.

[0091] Rf=0.45 (cyclohexane/ethyl acetate 70/30) NMR (CDCl₃) 3.95 s OCH₃4.84 ml OH 7.16 d H₅ 7.29 dd H₇ 7.40 d, 7.68 dd, 8.29 d H₃, H₄, H₈ 6.93;7.40 H of Ph-OH

Stage F: Deprotection: demethylation5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol

[0092] 300 mg of the product obtained in the preceding stage and 3 g ofpyridinium hydrochloride are mixed together under an inert atmosphereand the reaction medium is heated for 2 hours at 200° C. After havingpoured the reaction medium into 30 ml of water, extraction is carriedout with ethyl acetate, followed by washing with water, drying,filtering and evaporation under reduced pressure. The crude product ispurified by chromatography eluting with a dichloromethane/ether mixture95/5. 120 mg of pure expected product is obtained.

[0093] Rf=0.20 (cyclohexane/ethyl acetate 70/30) M.p. = 254°0 C. NMR(CDCl₃) 7.20 to 7.40 m, H of naphthyl 7.71 dl, 8.13 dl 6.87; 7.30 H ofPh-OH 9.57 s; 10.00 s OH (Ph-OH, Naphth-OH)

EXAMPLE 3 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol

[0094] The operation is carried out in a similar manner to Example 2starting with 100 mg of 1,5-dichloro-2-hydroxy-6-methoxy-naphthalene(obtained by the action of 0.35 ml of sulphuryl chloride on 350 mg ofthe product of Example 2 Stage A in 20 ml of dichloromethane with ayield of 100%) and by using the boronic acid of Preparation 1, 15 mg ofpure expected product is obtained.

[0095] Rf=0.60 (cyclohexane/ethyl acetate 50/50) NMR (CDCl₃) 7.40; 7.53d; 8.04 d; 8.30 d H of naphthyl 6.94; 7.430 H of Ph-OH 4.85 wm; 5.92 wm(Ph-OH, Naphth-OH)

Pharmaceutical Composition

[0096] Tablets were prepared corresponding to the following generalformula: product of Example 2  50 mg Excipient (talc, starch, magnesiumstearate) qs for a tablet completed at 120 mg

Pharmacological Study of the Products of the Invention Human OestrogenReceptor (HOR)

[0097] A cytosolic extract of SF9 cells containing the recombinant humanoestrogen receptor is obtained by overexpression in aninsect-Baculovirus cell system, according to the general methodologydescribed by N. R. WEBB et al. (Journal of Methods in Cell and MolecularBiology, (1990) Vol.2 No. 4, 173-188) and the application of which isdescribed for the expression of human hormonal receptors, for examplethe human glucocorticoid receptor (G. SRINIVASAN et al. MolecularEndocrinology (1990) vol 4 No. 2 209-216).

[0098] The BaculoGold Transfection Kit (PharMingen, reference 21000K) isused to generate the recombinant baculovirus containing the cDNAfragment described in the expression vector HEGO by L. TORA et al. (TheEMBO Journal (1989) vol. 8 No. 7 1981-1986), containing the regioncoding for the wild-type human oestrogen receptor with a glycine inposition 400.

[0099] The recombinant virus thus obtained is used to express theoestrogen receptor in the SF9 insect cells (ATCC CRL1711), according tothe known methodology mentioned previously.

[0100] 2*10⁷ SF9 cells are cultured in a 175 cm² “Falcon” flask in theTNM-FH “SIGMA” medium supplemented by 10% of foetal calf serum (FCS) andby 50 microgram/ml of gentamycin. After infection then incubation at 27°C. for 40 to 42 hours, the cells are lysed in 1 ml of lysis buffer (Tris20 mM-HCl pH8, EDTA 0.5 mM, DTT 2 mM, Glycerol 20%, KCl 400 mM) with afreezing-thawing cycle which is repeated another two times. Thesupernatant, containing the recombinant human oestrogen receptor is keptin liquid nitrogen by 0.5 ml doses.

[0101] The supernatant is incubated at 0° C. for 24 hours with aconstant concentration (T) of tritiated oestradiol in the presence ofincreasing concentrations of either unlabelled oestradiol(0-1000×10⁻⁹M), or of unlabelled product to be tested (0-25000×10⁻⁹M).The concentration of bound tritiated oestradiol (B) is then measured ineach incubate by the technique of adsorption with carbon dextran.

Calculation of the Relative Bond Affinity (RBA)

[0102] The following two curves are drawn: the percentage of boundtritiated hormone 100×B/B0 as a function of the logarithm of theconcentration of unlabelled reference hormone or as a function of theconcentration of unlabelled test product.

[0103] The straight line of the equation

I ₅₀=(BO/BO+B min)/2=100 (1+Bmin/BO)=50 (1+Bmin/BO)

[0104] is determined.

[0105] BO=concentration of bound tritiated hormone in the absence of anyunlabelled product.

[0106] B=concentration of bound tritiated hormone in the presence of aconcentration X of unlabelled product.

[0107] B min=concentration of bound tritiated hormone for an incubationof this tritiated hormone at a concentration (T) in the presence of alarge excess of unlabelled reference hormone (1000×10⁹⁻M) for the humanreceptor.

[0108] The intersections of the straight line I₅₀ and the curves allowthe evaluation of the concentrations of unlabelled reference hormone(CH) and of the unlabelled test product (CX) which inhibit by 50% thebinding of the tritiated hormone on the receptor.

[0109] The relative bond affinity (RBA) of the test product iscalculated by the equation:

RBA=100(CH)/(CX).

[0110] The results obtained are as follows: HOR oestradiol = 100Examples 24 hours 1 28 2 49 3 5

Conclusion

[0111] While these products have an affinity which is 2 to 20 timesweaker than that of oestradiol, the fixation on the oestrogen receptoris a new fact for this family of products.

1) The compounds of general formula (I)

in which [X] represents the following aromatic carbocycles:

and in which R₁ represents an alkyl radical containing from 1 to 4carbon atoms or a hydrogen atom, R₂ represents an alkyl radicalcontaining from 1 to 4 carbon atoms or a hydrogen atom, R₃ represents ahydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms,R₄ in para or meta position represents a hydrogen atom, a halogen atom,a hydroxyl radical, an alkyl, alkenyl or alkynyl radical containing atmost 4 carbon atoms, an alkoxy, alkylthio radical in which alkylcontains from 1 to 4 carbon atoms, an —NR_(A)R_(B) group in which R_(A)and R_(B) identical or different represent a hydrogen atom, an alkylradical containing from 1 to 4 carbon atoms or form together with thenitrogen to which they are linked a saturated heterocycle with 5 or 6members optionally containing a second heteroatom chosen from nitrogen,oxygen and sulphur, their —NR_(A)R_(B) group being optionally inoxidized form, a group of general formula —O—(CH₂)_(n—NR) _(A)R_(B) inwhich n is an integer which varies from 2 to 7 and in which —NR_(A)R_(B)is as defined previously, R₅ represents a hydrogen atom or a halogenatom, R₆ and R₇ identical or different represent a hydrogen atom, ahalogen atom, an alkyl radical containing from 1 to 4 carbon atoms, or aphenyl radical optionally substituted in meta or para position by an R₄radical as defined previously as well as the addition salts with acidsor bases, with the exception of the compounds of formula (I) in which[X] represents the group (A) in which R1, R₂, R₃ are hydrogen atoms andR₄ represents a hydroxyl radical and those in which [X] represents thegroup (B) in which R₅ R₆ and R₇ are hydrogen atoms or R₅ and R₆ arehydrogen atoms and R₇ represents an alkyl radical containing from 1 to 4carbon atoms. 2.- The compounds of general formula (I) as defined inclaim 1 in which [X] is the aromatic carbocycle of general formula (A).3.- The compounds of general formula (I) as defined in claim 1 in which[X] is the aromatic carbocycle of general formula (B). 4.- The compoundsof general formula (I) as defined in claim 1 or 2, corresponding togeneral formula (I′):

in which R′₁, R′₂ and R′₃ represent a hydrogen atom or an alkyl radicalcontaining from 1 to 4 carbon atoms, R′₄ in meta or para positionrepresents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkylradical, an —NR_(A)R_(B) group or an O(CH₂)_(n)—NR_(A)R_(B) group, n,R_(A) and R_(B) being as defined previously, as well as the additionsalts with acids or bases. 5.- The compounds corresponding to generalformula (I′) as defined in claim 4 in which R′₁, R′₂ and R′₃ arehydrogen atoms. 6.- The compounds of general formula (I) as defined inclaim 1 or 3, in which R₆ represents a halogen atom or a—O—(CH₂)₂—N(CH₃)₂ group and R₇ represents a hydrogen atom. 7.- Thefollowing compounds of general formula (I) as defined in claims 1 to 6:5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol, 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol. 8.- A preparation processfor the products of formula (I) as defined in claim 1, characterized inthat a product of formula (II):

in which [X] is as defined in claim 1, P′ represents a protective group,and G represents a halogen atom or an OSO₂CF₃ group is subjected to theaction, in the presence of a catalyst, of a product of formula (III):

 in which Y represents a halogen atom, a B(OH)₂ group or an Sn(R)₃group, in which R represents an alkyl group containing from 1 to 8carbon atoms and P represents a protective group, in order to obtain aproduct of formula (IV):

 in which P, P′ and [X] have the same meaning as previously, whichproduct of formula (IV) is subjected to one or more deprotectionreactions in order to obtain the expected product of formula (I) which,if appropriate, is subjected to the action of an acid or base in orderto obtain the corresponding salt. 9.- A preparation process for theproducts of formula (I) as defined in claim 2, characterized in that aproduct of formula (V):

in which R₄ is as defined in claim 1, and in which P is a protectivegroup is subjected to the action of the methylvinylketone of generalformula (VI):

 in which R₁, R₂ and R₃ are as defined in claim 1, in order to obtainthe product of formula (VII):

in which R₁, R₂, R₃, R₄ and P are as defined previously, which issubjected to the action of a dehydration and aromatization reagent inorder to obtain the product of formula (VIII):

 in which R₁, R₂, R₃, R₄ and P are as in claim 1, which is subjected tothe action of a deprotection reagent in order to obtain the products offormula (I) which, if desired, is subjected to the action of an acid orbase in order to obtain the corresponding salt. 10.- As medicaments, theproducts of general formula (I) as defined in claim 1, as well as theiraddition salts with pharmaceutically acceptable acids or bases. 11.- Asmedicaments the products of general formula (I) as defined in any one ofclaims 2 to 6, as well as their addition salts with pharmaceuticallyacceptable acids or bases. 12.- As medicaments the products of generalformula (I) as defined in claim
 7. 13.- Pharmaceutical compositionscontaining at least one of the medicaments as defined in any one 7 ofclaims 10 to 12 as active ingredient. 14.- As new industrial productsthe products of general formula (IV), (V), (VII) and (VIII) as definedpreviously, with the exception of the products of formula (V) in whichR₄ is an alkyloxy containing from 1 to 4 carbon atoms or a halogen atomand P is an alkyl radical containing from 1 to 4 carbon atoms and withthe exception of the products of formula (VII) and (VIII) in which R₄ isa methoxy radical, P is a methyl radical and R₁, R₂ and R₃ are hydrogenatoms, and with the exception of the products of formula (IV) in which Pand P′ are methyl or acyl radicals and X represents the group B in whichR₅, R₆ and R₇ are hydrogen atoms.